Download Oxycodone-Naloxone Acino Prolonged

SUMMARY OF PRODUCT CHARACTERISTICS
1
1.
NAME OF THE MEDICINAL PRODUCT
Oxycodone/Naloxone Acino 5 mg/2.5 mg prolonged-release tablets
Oxycodone/Naloxone Acino 10 mg/5 mg prolonged-release tablets
Oxycodone/Naloxone Acino 20 mg/10 mg prolonged-release tablets
Oxycodone/Naloxone Acino 40 mg/20 mg prolonged-release tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
5 mg/2.5 mg prolonged-release tablets
Each prolonged-release tablet contains 5 mg of oxycodone hydrochloride equivalent to 4.5 mg oxycodone
and naloxone hydrochloride dihydrate equivalent to 2.5 mg naloxone hydrochloride and 2.25 mg naloxone.
Excipient with known effect: Each prolonged-release tablet contains 16.0 mg lactose.
10 mg/5 mg prolonged-release tablets
Each prolonged-release tablet contains 10 mg of oxycodone hydrochloride equivalent to 9.0 mg oxycodone
and naloxone hydrochloride dihydrate equivalent to 5.0 mg naloxone hydrochloride and 4.5 mg naloxone.
Excipient with known effect: Each prolonged-release tablet contains 32.0 mg lactose.
20 mg/10 mg prolonged-release tablets
Each prolonged-release tablet contains 20 mg of oxycodone hydrochloride equivalent to 18.0 mg oxycodone
and naloxone hydrochloride dihydrate equivalent to 10.0 mg naloxone hydrochloride and 9.0 mg naloxone.
< 40 mg/20 mg prolonged-release tablets
Each prolonged-release tablet contains 40 mg of oxycodone hydrochloride equivalent to 36.0 mg
oxycodone and naloxone hydrochloride dihydrate equivalent to 20.0 mg naloxone hydrochloride and 18.0
mg naloxone.
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Prolonged-release tablet
Oxycodone/Naloxone Acino 5 mg/2.5 mg prolonged-release tablet
Light blue, round, convex, film-coated tablets with a nominal diameter of 7.2 mm.
Oxycodone/Naloxone Acino 10 mg/5 mg prolonged-release tablet
White to off-white, oval, convex, film-coated tablets with a nominal length of 13.2 mm.
Oxycodone/Naloxone Acino 20 mg/10 mg prolonged-release tablet
Pink, oval, convex, film-coated tablets with a nominal length of 10.2 mm.
Oxycodone/Naloxone Acino 40 mg/20 mg prolonged-release tablet
Light orange to ochre, oval, convex, film-coated tablets with a nominal length of 13.2 mm.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
Severe pain, which can be adequately managed only with opioid analgesics.
Second-line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome
2
after failure of dopaminergic therapy.
The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of
oxycodone at opioid receptors locally in the gut.
Oxycodone/Naloxone Acino is indicated in adults.
4.2
Posology and method of administration
Posology
Analgesia
The analgesic efficacy of Oxycodone/Naloxone Acino is equivalent to oxycodone hydrochloride prolongedrelease formulations.
The dosage should be adjusted to the intensity of pain and the sensitivity of the individual patient. Unless
otherwise prescribed, Oxycodone/Naloxone Acino should be administered as follows:
Adults
The usual starting dose for an opioid naïve patient is 10 mg/5 mg of oxycodone hydrochloride/naloxone
hydrochloride at 12 hourly intervals.
Patients already receiving opioids may be started on higher doses of Oxycodone/Naloxone Acino depending
on their previous opioid experience.
Oxycodone/Naloxone Acino 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy and
individual dose adjustment.
The maximum daily dose of Oxycodone/Naloxone Acino is 160 mg oxycodone hydrochloride and 80 mg
naloxone hydrochloride. The maximum daily dose is reserved for patients who have previously been
maintained on a stable daily dose of oxycodone/naloxone and who have become in need of an increased
dose. Special attention should be given to patients with compromised renal function and patients with mild
hepatic impairment if an increased dose is considered. For patients requiring higher doses of
Oxycodone/Naloxone Acino, administration of supplemental prolonged-release oxycodone hydrochloride at
the same time intervals should be considered, taking into account the maximum daily dose of 400 mg
prolonged-release oxycodone hydrochloride. In the case of supplemental oxycodone hydrochloride dosing,
the beneficial effect of naloxone hydrochloride on bowel function may be impaired.
After complete discontinuation of therapy with Oxycodone/Naloxone Acino with a subsequent switch to
another opioid a worsening of the bowel function can be expected.
Some patients taking Oxycodone/Naloxone Acino according to a regular time schedule require immediaterelease analgesics as “rescue” medication for breakthrough pain. Oxycodone/Naloxone Acino is a prolongedrelease formulation and therefore not intended for the treatment of breakthrough pain. For the treatment of
breakthrough pain, a single dose of “rescue medication” should approximate one sixth of the equivalent daily
dose of oxycodone hydrochloride. The need for more than two “rescues” per day is usually an indication that
the dose of Oxycodone/Naloxone Acino requires upward adjustment. This adjustment should be made every
1-2 days in steps of 5 mg/2.5 mg twice daily, or where necessary 10 mg/5 mg, oxycodone
hydrochloride/naloxone hydrochloride until a stable dose is reached. The aim is to establish a patient-specific
twice daily dose that will maintain adequate analgesia and make use of as little rescue medication as possible
for as long as pain therapy is necessary.
Oxycodone/Naloxone Acino is taken at the determined dosage twice daily according to a fixed time
schedule. While symmetric administration (the same dose mornings and evenings) subject to a fixed time
3
schedule (every 12 hours) is appropriate for the majority of patients, some patients, depending on the
individual pain situation, may benefit from asymmetric dosing tailored to their pain pattern. In general, the
lowest effective analgesic dose should be selected.
In non-malignant pain therapy, daily doses of up to 40 mg/20 mg oxycodone hydrochloride/naloxone
hydrochloride are usually sufficient, but higher doses may be needed.
Restless legs syndrome
Oxycodone/Naloxone Acino is indicated for patients suffering from RLS for at least 6 months. RLS
symptoms should be present daily and during daytime (≥ 4 days/week). Oxycodone/Naloxone Acino should
be used after failure of previous dopaminergic treatment. Dopaminergic treatment failure is defined as
inadequate initial response, a response that has become inadequate with time, occurrence of augmentation or
unacceptable tolerability despite adequate doses. Previous treatment with at least one dopaminergic
medicinal product should have lasted in general 4 weeks. A shorter period might be acceptable in case of
unacceptable tolerability with dopaminergic therapy.
The dosage should be adjusted to the sensitivity of the individual patient.
Treatment of patients with restless legs syndrome with Oxycodone/Naloxone Acino should be under the
supervision of a clinician with experience in the management of restless legs syndrome.
Unless otherwise prescribed, Oxycodone/Naloxone Acino should be administered as follows:
Adults
The usual starting dose is 5 mg/2.5 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly
intervals.
Titration on a weekly basis is recommended in case higher doses are required. The mean daily dose in the
pivotal study was 20 mg/10 mg oxycodone hydrochloride/naloxone hydrochloride. Some patients may
benefit from higher daily doses up to a maximum of 60 mg/30 mg oxycodone hydrochloride/naloxone
hydrochloride.
Oxycodone/Naloxone Acino is taken at the determined dosage twice daily according to a fixed time
schedule. While symmetric administration (the same dose mornings and evenings) subject to a fixed time
schedule (every 12 hours) is appropriate for the majority of patients, some patients, depending on the
individual situation, may benefit from asymmetric dosing tailored to the individual patient. In general, the
lowest effective dose should be selected.
Analgesia / Restless legs syndrome
Elderly patients
As for younger adults the dosage should be adjusted to the intensity of the pain or RLS symptoms and the
sensitivity of the individual patient.
Patients with impaired hepatic function
A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in
patients with hepatic impairment. Naloxone concentrations were affected to a higher degree than oxycodone
(see section 5.2). The clinical relevance of a relative high naloxone exposure in hepatic impaired patients is
yet not known. Caution must be exercised when administering Oxycodone/Naloxone Acino to patients with
mild hepatic impairment (see section 4.4). In patients with moderate and severe hepatic impairment
Oxycodone/Naloxone Acino is contraindicated (see section 4.3).
4
Patients with impaired renal function
A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in
patients with renal impairment (see section 5.2). Naloxone concentrations were affected to a higher degree
than oxycodone. The clinical relevance of a relative high naloxone exposure in renal impaired patients is yet
not known. Caution should be exercised when administering Oxycodone/Naloxone Acino to patients with
renal impairment (see section 4.4).
Paediatric population
The safety and efficacy of Oxycodone/Naloxone Acino in children aged below 18 years has not been
established. No data are available.
Method of administration
Oral use.
Oxycodone/Naloxone Acino is taken in the determined dosage twice daily in a fixed time schedule.
The prolonged-release tablets may be taken with or without food with sufficient liquid. The prolongedrelease tablets must be swallowed whole, and not broken, chewed or crushed.
Duration of use
Oxycodone/Naloxone Acino should not be administered for longer than absolutely necessary. If long-term
treatment is necessary in view of the nature and severity of the illness, careful and regular monitoring is
required to establish whether and to what extent further treatment is necessary.
Analgesia
When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually (see
section 4.4).
Restless legs syndrome
At least every three months during therapy with Oxycodone/Naloxone Acino patients should be clinically
evaluated. Treatment should only be continued if Oxycodone/Naloxone Acino is considered effective and the
benefit is considered to outweigh adverse effects and potential harms in individual patients. Prior to
continuation of RLS treatment beyond 1 year a discharge regimen by gradually tapering down of
Oxycodone/Naloxone Acino over a period of approximately one week should be considered to establish if
continued treatment with Oxycodone/Naloxone Acino is indicated.
When a patient no longer requires opioid therapy cessation of treatment by tapering down over a period of
approximately one week is recommended in order to reduce the risk of a withdrawal reaction (see section
4.4).
4.3








Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1,
Any situation where opioids are contraindicated,
Severe respiratory depression with hypoxia and/or hypercapnia,
Severe chronic obstructive pulmonary disease,
Cor pulmonale,
Severe bronchial asthma,
Non-opioid induced paralytic ileus,
Moderate to severe hepatic impairment.
5
Additionally, for restless legs syndrome:
History of opioid abuse.
4.4
Special warnings and precautions for use
The major risk of opioid excess is respiratory depression.
Caution must be exercised when administering Oxycodone/Naloxone Acino to elderly or infirm patients,
patients with opioid-induced paralytic ileus, patients presenting severely impaired pulmonary function,
patients with sleep apnoea, myxoedema, hypothyroidism, Addison’s disease (adrenal cortical insufficiency),
toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypotension,
hypertension, pre-existing cardiovascular diseases, head injury (due to the risk of increased intracranial
pressure), epileptic disorder or predisposition to convulsions, or patients taking MAO inhibitors.
Caution is advised in treating restless legs syndrome patients with additional sleep apnoea syndrome with
oxycodone/naloxone due to the additive risk of respiratory depression. No data about the risk exist because
in the clinical trial patients with sleep apnoea syndrome were excluded.
Caution must also be exercised when administering Oxycodone/Naloxone Acino to patients with mild
hepatic or renal impairment. A careful medical monitoring is particularly necessary for patients with severe
renal impairment.
Diarrhoea may be considered as a possible effect of naloxone.
In patients under long-term opioid treatment with higher doses of opioids, the switch to
Oxycodone/Naloxone Acino can initially provoke withdrawal symptoms. Such patients may require specific
attention.
Oxycodone/Naloxone Acino is not suitable for the treatment of withdrawal symptoms.
During long-term administration, the patient may develop tolerance to the medicinal product and require
higher doses to maintain the desired effect. Chronic administration of Oxycodone/Naloxone Acino may lead
to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy
with Oxycodone/Naloxone Acino is no longer required, it may be advisable to reduce the daily dose
gradually in order to avoid the occurrence of withdrawal syndrome (see section 4.2).
There is potential for development of psychological dependence (addiction) to opioid analgesics, including
Oxycodone/Naloxone Acino. Oxycodone/Naloxone Acino should be used with particular care in patients
with a history of alcohol and drug abuse. Oxycodone alone has an abuse profile similar to other strong
agonist opioids.
In order not to impair the prolonged-release characteristic of the prolonged-release tablets, the prolongedrelease tablets must be taken whole and must not be broken, chewed or crushed. Breaking, chewing or
crushing the prolonged-release tablets for ingestion leads to a faster release of the active substances and the
absorption of a possibly fatal dose of oxycodone (see section 4.9).
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore, a reduction of the dose or termination of therapy may be
considered. Because of possible additive effects, caution should be advised when patients are taking other
sedating medicinal products in combination with Oxycodone/Naloxone Acino (see sections 4.5 and 4.7).
Concomitant use of alcohol and Oxycodone/Naloxone Acino may increase the undesirable effects of
Oxycodone/Naloxone Acino. Concomitant use should be avoided
Studies have not been performed on the safety and efficacy of oxycodone/naloxone in children and
6
adolescents below the age of 18 years. Therefore, their use in children and adolescents under 18 years of age
is not recommended.
There is no clinical experience in patients with cancer associated to peritoneal carcinomatosis or with subocclusive syndrome in advanced stages of digestive and pelvic cancers. Therefore, the use of
Oxycodone/Naloxone Acino in this population is not recommended
Oxycodone/Naloxone Acino is not recommended for pre-operative use or within the first 12-24 hours postoperatively. Depending on the type and extent of surgery, the anaesthetic procedure selected, other comedication and the individual condition of the patient, the exact timing for initiating post-operative treatment
with Oxycodone/Naloxone Acino depends on a careful risk-benefit assessment for each individual patient.
Any abuse of Oxycodone/Naloxone Acino by drug addicts is strongly discouraged.
If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin,
morphine, or methadone, the broken, chewed or crushed tablet is expected to produce marked withdrawal
symptoms - because of the opioid receptor antagonist characteristics of naloxone - or to intensify withdrawal
symptoms already present (see section 4.9).
Oxycodone/Naloxone Acino consists of a dual-polymer matrix, intended for oral use only. Abusive
parenteral injections of the prolonged-release tablet constituents (especially talc) can be expected to result in
local tissue necrosis and pulmonary granulomas or may lead to other serious, potentially fatal undesirable
effects.
The empty prolonged-release tablet matrix may be visible in the stool.
Oxycodone/Naloxone Acino 5 mg/2.5 mg and 10 mg/5 mg prolonged-release tablets contain lactose. Patients
with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption should not take Oxycodone/Naloxone Acino 5 mg/2.5 mg and 10 mg/5 mg.
4.5
Interaction with other medicinal products and other forms of interaction
Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, antidepressants,
phenothiazines, neuroleptics, antihistamines and antiemetics) may enhance the CNS-depressant effect (e.g.
respiratory depression) of Oxycodone/Naloxone Acino.
Alcohol may enhance the pharmacodynamic effects of Oxycodone/Naloxone Acino; concomitant use should
be avoided.
Clinically relevant changes in International Normalized Ratio (INR or Quick-value) in both directions have
been observed in individuals if oxycodone and coumarin anticoagulants are co-applied.
Oxycodone is metabolised primarily via the CYP3A4 pathways and partly via the CYP2D6 pathway (see
section 5.2). The activities of these metabolic pathways may be inhibited or induced by various coadministered drugs or dietary elements. Oxycodone/Naloxone Acino doses may need to be adjusted
accordingly.
CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin, telithromycin), azoleantifungal agents (e.g. ketoconazole, voriconazole, itraconazole, posaconazole), protease inhibitors (e.g.
ritonavir, indinavir, nelfinavir, saquinavir), cimetidine and grapefruit juice may cause decreased clearance of
oxycodone which could lead to an increase in oxycodone plasma concentrations. A reduction in the dose of
Oxycodone/Naloxone Acino and subsequent re-titration may be necessary.
CYP3A4 inducers, such as rifampicin, carbamazepine, phenytoin and St. John’s Wort, may induce the
metabolism of oxycodone and cause increased clearance of the drug, resulting in a decrease in oxycodone
7
plasma concentrations. Caution is advised and further titration may be necessary to reach an adequate level
of symptom control.
Theoretically, medicinal products that inhibit CYP2D6 activity, such as paroxetine, fluoxetine and quinidine,
may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma
concentrations. Concomitant administration with CYP2D6 inhibitors had an insignificant effect on the
elimination of oxycodone and also had no influence on the pharmacodynamic effects of oxycodone.
In vitro metabolism studies indicate that no clinically relevant interactions are to be expected between
oxycodone and naloxone.
The likelihood of clinically relevant interactions between paracetamol, acetylsalicylic acid or naltrexone and
the combination of oxycodone and naloxone in therapeutic concentrations is minimal.
4.6
Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of oxycodone/naloxone in pregnant women and during childbirth. Limited
data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of
congenital abnormalities. For naloxone, insufficient clinical data on exposed pregnancies are available.
However, systemic exposure of the women to naloxone after use of oxycodone/naloxone prolonged-release
tablets is relatively low (see section 5.2). Both oxycodone and naloxone pass into the placenta. Animal
studies have not been performed with oxycodone and naloxone in combination (see section 5.3). Animal
studies with oxycodone or naloxone administered as single drugs have not revealed any teratogenic or
embryotoxic effects.
Long-term administration of oxycodone during pregnancy may lead to withdrawal symptoms in the
newborn. If administered during childbirth, oxycodone may evoke respiratory depression in the newborn.
Oxycodone/Naloxone Acino should only be used during pregnancy if the benefit outweighs the possible
risks to the unborn child or neonate.
Breastfeeding
Oxycodone passes into the breast milk. A milk-plasma concentration ratio of 3.4:1 was measured and
oxycodone effects in the suckling infant are therefore conceivable. It is not known whether naloxone also
passes into the breast milk. However, after use of oxycodone/naloxone prolonged-release tablets systemic
naloxone levels are very low (see section 5.2). A risk to the suckling child cannot be excluded in particular
following intake of multiple doses of Oxycodone/Naloxone Acino by the breastfeeding mother.
Breastfeeding should be discontinued during treatment with Oxycodone/Naloxone Acino.
Fertility
There are no data with respect to fertility.
4.7
Effects on ability to drive and use machines
Oxycodone/Naloxone Acino has moderate influence on the ability to drive and use machines. This is
particularly likely at the beginning of treatment with Oxycodone/Naloxone Acino, after dose increase or
product rotation and if Oxycodone/Naloxone Acino is combined with other CNS-depressant agents. Patients
stabilised on a specific dosage will not necessarily be restricted. Therefore, patients should consult with their
physician as to whether driving or the use of machinery is permitted.
Patients being treated withOxycodone/Naloxone Acino and presenting with somnolence and/or sudden sleep
episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put
8
themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes
and somnolence have resolved (see also sections 4.4 and 4.5).
4.8
Undesirable effects
The following frequencies are the basis for assessing undesirable effects:
Very common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Rare (≥ 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)
Not known (cannot be estimated from the available data)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Undesirable effects in the treatment of pain
System organ
class MedDRA
Immune system
disorders
Metabolism and
nutritional
disorders
Psychiatric
disorders
Nervous system
disorders
Eye disorder
Ear and labyrinth
disorder
Cardiac disorders
Vascular
disorders
Respiratory,
thoracic and
mediastinal
disorders
Common
Uncommon
Rare
Not known
Hypersensitivity
Appetite decreased
up to loss of
appetite
Insomnia
Abnormal
thinking
Anxiety
Confusion
Depression
Nervousness
Restlessness
Dizziness
Convulsions1
Headache
Disturbance in
Somnolence
attention
Speech disorder
Syncope
Tremor
Visual impairment
Vertigo
Hot flush
Angina pectoris2 Tachycardia
Palpitations
Blood pressure
decreased Blood
pressure increased
Dyspnoea
Yawning
Rhinorrhoea
Cough
9
Euphoric mood
Hallucination
Nightmares
Paraesthesia
Sedation
Respiratory
depression
Gastrointestinal
disorders
Abdominal pain
Constipation
Diarrhoea
Dry mouth
Dyspepsia
Vomiting
Nausea
Flatulence
Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorder
Musculoskeletal
and connective
tissue disorder
Renal and urinary
disorders
Reproductive
system and breast
disorders
General disorders
and administration
site conditions
Abdominal
distention
Tooth disorder
Eructation
Hepatic enzymes
increased
Biliary colic
Pruritus
Skin reactions
Hyperhidrosis
Muscle spasms
Muscle twitching
Myalgia
Micturition
urgency
Urinary retention
Erectile
dysfunction
Asthenic
conditions
Fatigue
Investigations
Chest pain
Chills
Drug withdrawal
syndrome
Malaise
Pain
Oedema
peripheral
Weight decreased
Weight increased
Injury, poisoning,
Injuries from
and procedural
accidents
complications
1
particularly in persons with epileptic disorder or predisposition to convulsions
2
particularly in patients with history of coronary artery disease
For the active substance oxycodone hydrochloride, the following additional undesirable effects are known:
Due to its pharmacological properties, oxycodone hydrochloride may cause respiratory depression, miosis,
bronchial spasm and spasms of nonstriated muscles as well as suppress the cough reflex.
System organ
class MedDRA
Infections and
infestations
Immune system
disorders
Metabolism and
nutritional
disorders
Common
Uncommon
Rare
Not known
Herpes simplex
Anaphylactic
responses
Dehydration
10
Appetite
increased
Psychiatric
disorders
Altered mood
and personality
changes
Decreased
activity
Psychomotor
hyperactivity
Nervous system
disorders
Ear and labyrinth
disorders
Vascular
disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders
Agitation
Perception
disturbances (e.g.
derealisation)
Libido reduced
Drug dependence
Impaired
concentration
Migraine
Dysgeusia
Hypertonia
Involuntary muscle
contractions
Hypoaesthesia
Abnormal coordination
Hearing impaired
Vasodilation
Dysphonia
Hiccups
Hepatobiliary
disorders
Skin and
subcutaneous tissue
disorders
Renal and urinary Dysuria
disorders
Reproductive
system and breast
disorders
General disorders
and administration
site conditions
Dysphagia
Ileus
Mouth ulceration
Stomatitis
Melaena,
Gingival bleeding
Cholestasis
Dry skin
Urticaria
Amenorrhoea
Oedema
Thirst
Drug tolerance
Undesirable effects in the treatment of restless legs syndrome
The list below reflects the adverse drug reactions seen with oxycodone hydrochloride/naloxone
hydrochloride in a 12-week, randomised, placebo-controlled clinical trial comprising a total of 150 patients
on oxycodone hydrochloride/naloxone hydrochloride and 154 patients on placebo with daily dosages
between 10 mg/5 mg and 80 mg/40 mg oxycodone hydrochloride/naloxone hydrochloride. Adverse drug
reactions associated with oxycodone/naloxone prolonged-release tablets in pain not observed in RLS study
population were added with the frequency of not known.
System organ
class MedDRA
Very Common
Common
Uncommon
11
Not known
Immune system
disorders
Metabolism and
nutrition disorders
Hypersensitivity
Appetite decreased
up to loss of
appetite
Insomnia
Libido
Depression
Decreased
Sleep attacks
Psychiatric
disorders
Nervous system
disorders
Headache
Somnolence
Eye disorders
Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
Convulsions1
Sedation Speech
disorder Syncope
Angina pectoris2
Palpitations
Tachycardia
Hot flush
Blood pressure
decreased
Blood pressure
increased
Respiratory
thoracic and
mediastinal
disorders
Gastrointestinal
disorders
Dysgeusia
Visual
impairment
Vertigo
Ear and labyrinth
disorders
Cardiac disorders
Vascular
disorders
Dizziness,
Disturbance in
attention Tremor
Paraesthesia
Abnormal
thinking Anxiety
Confusion
Nervousness
Restlessness
Euphoric mood
Hallucination
Nightmares
Dyspnoea
Constipation
Nausea
Hyperhidorosis
Abdominal pain
Dry mouth
Vomiting
Hepatic enzymes
increased3
Pruritus
Skin reactions
Flatulence
Cough
Rhinorrhoea
Respiratory
depression
Yawning
Abdominal
Distention
Diarrhoea
Dyspepsia
Eructation
Tooth disorder
Biliary colic
Muscle spasms
Muscle twitching
Myalgia
Renal and urinary
disorders
Reproductive
systems and breast
disorders
Micturition
urgency
Urinary retention
Erectile
dysfunction
12
General disorders Fatigue
and administration
site conditions
Chest pain
Chills
Thirst Pain
Drug withdrawal Malaise
syndrome
Oedema
peripheral
Investigation
Injury, poisoning
and procedural
complications
1
particularly in persons with epileptic disorder or predisposition to convulsions
2
particularly in patients with history of coronary artery disease
3
alanine aminotransferase increased, gamma-glutamyl transferease increased
Weight decreased
Weight increased
Injuries from
accidents
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9
Overdose
Symptoms of intoxication
Depending on the history of the patient, an overdose of Oxycodone/Naloxone Acino may be manifested by
symptoms that are either triggered by oxycodone (opioid receptor agonist) or by naloxone (opioid receptor
antagonist).
Symptoms of oxycodone overdose include miosis, respiratory depression, somnolence progressing to stupor,
skeletal muscle flaccidity, bradycardia as well as hypotension. Coma, non-cardiogenic pulmonary oedema
and circulatory failure may occur in more severe cases and may lead to a fatal outcome.
Symptoms of a naloxone overdose alone are unlikely.
Therapy of intoxication
Withdrawal symptoms due to an overdose of naloxone should be treated symptomatically in a closelysupervised environment.
Clinical symptoms suggestive of an oxycodone overdose may be treated by the administration of opioid
antagonists (e.g. naloxone hydrochloride 0.4-2 mg intravenously). Administration should be repeated at 2-3
minute intervals, as clinically necessary. It is also possible to apply an infusion of 2 mg naloxone
hydrochloride in 500 ml of 0.9% sodium chloride or 5% dextrose (0.004 mg/ml naloxone). The infusion
should be run at a rate aligned to the previously administered bolus doses and to the patient’s response.
Consideration may be given to gastric lavage.
Supportive measures (artificial ventilation, oxygen, vasopressors and fluid infusions) should be employed, as
necessary, to manage the circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may
require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary. Fluid and
electrolyte metabolism should be maintained.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
13
Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids, ATC code: N02AA55
Mechanism of action
Oxycodone and naloxone have an affinity for kappa, mu and delta opiate receptors in the brain, spinal cord
and peripheral organs (e.g. intestine). Oxycodone acts as opioid-receptor agonist at these receptors and binds
to the endogenous opioid receptors in the CNS. By contrast, naloxone is a pure antagonist acting on all types
of opioid receptors.
Pharmacodynamic effects
Because of the pronounced first-pass metabolism, the bioavailability of naloxone upon oral administration is
<3%, therefore a clinically relevant systemic effect is unlikely. Due to the local competitive antagonism of
the opioid receptor mediated oxycodone effect by naloxone in the gut, naloxone reduces the bowel function
disorders that are typical for opioid treatment.
Clinical efficacy and safety
Opioids can influence the hypothalamic-pituitary-adrenal or gonadal axes. Among the changes observed are
an increase of prolactin in the serum and a reduced level of cortisol and testosterone in the plasma. Clinical
symptoms may occur because of these hormone changes.
Preclinical studies show differing effects of natural opioids on components of the immune system. The
clinical significance of these findings is not known. It is not known whether oxycodone, a semi-synthetic
opioid, has similar effects on the immune system to natural opioids.
Analgesia
In a 12-weeks parallel-group double-blinded study in 322 patients with opioid-induced constipation, patients
who were treated with oxycodone hydrochloride-naloxone hydrochloride had on average one extra complete
spontaneous (without laxatives) bowel movement in the last week of treatment, compared to patients who
continued using similar doses of oxycodone hydrochloride prolonged release tablets (p<0.0001). The use of
laxatives in the first four weeks was significantly lower in the oxycodone-naloxone group compared to the
oxycodone monotherapy group (31% versus 55%, respectively, p<0.0001). Similar results were shown in a
study with 265 non-cancer patients comparing daily doses of oxycodone hydrochloride/naloxone
hydrochloride of 60 mg/30 mg to up to 80 mg/40 mg with oxycodone hydrochloride monotherapy in the
same dose range.
Restless legs syndrome
In a 12-week double-blind efficacy study, 150 patients with severe to very severe idiopathic restless legs
syndrome at randomisation were treated with oxycodone hydrochloride/naloxone hydrochloride. Severe
syndrome is defined as IRLS score between 21 and 30 and very severe as score between 31 and 40. Patients
showed a clinically relevant and a statistically significant improvement in mean IRLS score compared to
placebo during the entire treatment period with a decrease in the mean IRLS score of 5.9 points compared to
placebo at week 12 (assuming an effect similar to placebo completers for patients who discontinued the
study representing a very conservative approach). The onset of efficacy was demonstrated from as early as
week 1 of treatment. Similar results were shown for the RLS symptom severity improvement (as measured
by the RLS-6-Rating scale), in quality of life as measured by a QoL-RLS questionnaire, in sleep quality
(measured by MOS sleep scale), and for the proportion of IRLS score remitters. No subject had a confirmed
case of augmentation during the study.
5.2
Pharmacokinetic properties
Oxycodone hydrochloride
14
Absorption
Oxycodone has a high absolute bioavailability of up to 87% following oral administration.
Distribution
Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to
plasma protein.
Oxycodone crosses the placenta and may be detected in breast milk.
Biotransformation
Oxycodone is metabolised in the gut and the liver to noroxycodone and oxymorphone and to various
glucuronide conjugates. Noroxycodone, oxymorphone and noroxymorphone are produced via the
cytochrome P450 system. Quinidine reduces the production of oxymorphone in man without substantially
influencing the pharmacodynamics of oxycodone. The contribution of the metabolites to overall
pharmacodynamic effect is insignificant.
Elimination
Oxycodone and its metabolites are excreted in both urine and faeces.
Naloxone hydrochloride
Absorption
Following oral administration, naloxone has a very low systemic availability of < 3%.
Distribution
Naloxone passes into the placenta. It is not known whether naloxone also passes into breast milk.
Biotransformation and elimination
After parenteral administration, the plasma half-life is approximately one hour. The duration of action
depends upon the dose and route of administration, intramuscular injection producing a more prolonged
effect than intravenous doses. It is metabolised in the liver and excreted in the urine. The principal
metabolites are naloxone glucuronide, 6β-Naloxol and its glucuronide.
Oxycodone hydrochloride / naloxone hydrochloride combination (Oxycodone/Naloxone Acino)
Pharmacokinetic/pharmacodynamic relationships
The pharmacokinetic characteristics of oxycodone from oxycodone/naloxone hydrochloride prolongedrelease tablets is equivalent to those of prolonged-release oxycodone hydrochloride tablets administered
together with prolonged-release naloxone hydrochloride tablets.
All dosage strengths of Oxycodone/Naloxone Acino are interchangeable.
After the oral administration of oxycodone/naloxone hydrochloride prolonged-release tablets at the
maximum dose to healthy subjects, the plasma concentrations of naloxone are so low that it is not feasible to
carry out a pharmacokinetic analysis. To conduct a pharmacokinetic analysis naloxone-3-glucuronide as
surrogate marker is used, since its plasma concentration is high enough to measure.
Overall, following ingestion of a high-fat breakfast, the bioavailability and peak plasma concentration (Cmax)
15
of oxycodone were increased by an average of 16% and 30%, respectively, compared to administration in the
fasting state. This was evaluated as clinically not relevant, therefore oxycodone/naloxone hydrochloride
prolonged-release tablets may be taken with or without food (see section 4.2).
In vitro drug metabolism studies have indicated that the occurrence of clinically relevant interactions
involving oxycodone/naloxone hydrochloride prolonged-release tablets is unlikely.
Elderly patients
Oxycodone
For AUCτ of oxycodone, on average there was an increase to 118% (90% C.I.: 103, 135), for elderly
compared with younger volunteers. For Cmax of oxycodone, on average there was an increase to 114% (90%
C.I.: 102, 127). For Cmin of oxycodone, on average there was an increase to 128% (90% C.I.: 107, 152).
Naloxone
For AUCτ of naloxone, on average there was an increase to 182% (90% C.I.: 123, 270), for elderly compared
with younger volunteers. For Cmax of naloxone, on average there was an increase to 173% (90% C.I.: 107,
280). For Cmin of naloxone, on average there was an increase to 317% (90% C.I.: 142, 708).
Naloxone-3-glucuronide
For AUCτ of naloxone-3-glucuronide, on average there was an increase to 128% (90% C.I.: 113, 147), for
elderly compared with younger volunteers. For Cmax of naloxone-3-glucuronide, on average there was an
increase to 127% (90% C.I.: 112, 144). For Cmin of naloxone-3-glucuronide, on average there was an increase
to 125% (90% C.I.: 105, 148).
Patients with impaired hepatic function
Oxycodone
For AUCINF of oxycodone, on average there was an increase to 143% (90% C.I : 111, 184), 319% (90% C.I.:
248, 411) and 310% (90% C.I.: 241, 398) for mild, moderate and severe hepatically impaired subjects,
respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to
120% (90% C.I.: 99, 144), 201% (90% C.I.: 166, 242) and 191% (90% C.I.: 158, 231) for mild, moderate
and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of
oxycodone, on average there was an increase to 108% (90% C.I.: 70, 146), 176% (90% C.I.: 138, 215) and
183% (90% C.I.: 145, 221) for mild, moderate and severe hepatically impaired subjects, respectively,
compared with healthy volunteers.
Naloxone
For AUCt of naloxone, on average there was an increase to 411% (90% C.I.: 152, 1112), 11518% (90% C.I.:
4259, 31149) and 10666% (90% C.I.: 3944, 28847) for mild, moderate and severe hepatically impaired
subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an
increase to 193% (90% C.I.: 115, 324), 5292% (90% C.I: 3148, 8896) and 5252% (90% C.I.: 3124, 8830) for
mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.
Due to insufficient amount of data available t1/2Z and the corresponding AUCINF of naloxone were not
calculated. The bioavailability comparisons for naloxone were therefore based on AUCt values.
Naloxone-3-glucuronide
For AUCINF of naloxone-3-glucuronide, on average there was an increase to 157% (90% C.I.: 89, 279), 128%
(90% C.I.: 72, 227) and 125% (90% C.I.: 71, 222) for mild, moderate and severe hepatically impaired
subjects, respectively, compared with healthy volunteers. For Cmax of naloxone-3-glucuronide, on average
16
there was an increase to 141% (90% C.I.: 100, 197, 118% (90% C.I.: 84, 166) and a decrease to 98% (90%
C.I.: 70, 137) for mild, moderate and severe hepatically impaired subjects, respectively, compared with
healthy volunteers. For t1/2Z of naloxone-3-glucuronide, on average there was an increase to 117% (90% C.I.:
72, 161, a decrease to 77% (90% C.I.: 32, 121) and a decrease to 94% (90% C.I.: 49, 139) for mild, moderate
and severe hepatically impaired subjects, respectively, compared with healthy volunteers.
Patients with impaired renal function
Oxycodone
For AUCINF of oxycodone, on average there was an increase to 153% (90% C.I.: 130, 182), 166% (90% C.I.:
140, 196) and 224% (90% C.I.: 190, 266) for mild, moderate and severe renally impaired subjects,
respectively, compared with healthy volunteers. For Cmax of oxycodone, on average there was an increase to
110% (90% C.I.: 94, 129), 135% (90% C.I.: 115, 159) and 167% (90% C.I.: 142, 196) for mild, moderate
and severe renally impaired subjects, respectively, compared with healthy volunteers. For t1/2Z of oxycodone,
on average there was an increase to 149%, 123% and 142% for mild, moderate and severe renally impaired
subjects, respectively, compared with healthy volunteers.
Naloxone
For AUCt of naloxone, on average there was an increase to 2850% (90% C.I.: 369, 22042), 3910% (90%
C.I.: 506, 30243) and 7612% (90% C.I.: 984, 58871) for mild, moderate and severe renally impaired
subjects, respectively, compared with healthy volunteers. For Cmax of naloxone, on average there was an
increase to 1076% (90% C.I.: 154, 7502), 858% (90% C.I.: 123, 5981) and 1675% (90% C.I.: 240, 11676)
for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers.
Due to insufficient amount of data available t1/2Z and the corresponding AUCINF of naloxone were not
calculated. The bioavailability comparisons for naloxone were therefore based on AUCt values. The ratios
may have been influenced by the inability to fully characterize the naloxone plasma profiles for the healthy
subjects.
Naloxone-3-glucuronide
For AUCINF of naloxone-3-glucuronide, on average there was an increase to 220% (90% C.I.: 148, 327),
370% (90% C.I.: 249, 550) and 525% (90% C.I.: 354, 781) for mild, moderate and severe renally impaired
subjects, respectively, compared with healthy subjects. For Cmax of naloxone-3-glucuronide, on average there
was an increase to 148% (90% C.I.: 110, 197), 202% (90% C.I.: 151, 271) and 239% (90% C.I.: 179, 320)
for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For
t1/2Z of naloxone-3-glucuronide, on average there was no significant change between the renally impaired
subjects and the healthy subjects.
Abuse
To avoid damage to the prolonged-release properties of the tablets, Oxycodone/Naloxone Acino must not be
broken, crushed or chewed, as this leads to a rapid release of the active substances. In addition, naloxone has
a slower elimination rate when administered intranasally. Both properties mean that abuse of
Oxycodone/Naloxone Acino will not have the effect intended. In oxycodone-dependent rats, the intravenous
administration of oxycodone hydrochloride / naloxone hydrochloride at a ratio of 2:1 resulted in withdrawal
symptoms.
5.3
Preclinical safety data
There are no data from studies on reproductive toxicity of the combination of oxycodone and naloxone.
Studies with the single components showed that oyxcodone had no effect on fertility and early embryonic
development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations
in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when
17
individual fetuses were used in statistical evaluation, a dose-related increase in developmental variations was
observed (increased incidence of 27 presacral vertebrae, extra pairs of ribs). When these parameters were
statistically evaluated using litters, only the incidences of 27 presacral vertebrae was increased and only in
the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a
study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to
body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2
mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental
parameters nor on behavioural and reproductive indices. The standard oral reproduction toxicity studies with
naloxone show that at high oral doses naloxone was not teratogenic and/or embryo/fetotoxic, and does not
affect perinatal/postnatal development.
At very high doses (800 mg/kg/day) naloxone produced increased pup deaths in the immediate post-partum
period at dosages that produced significant toxicity in maternal rats (e.g., body weight loss, convulsions).
However, in surviving pups, no effects on development or behaviour were observed.
Long-term carcinogenicity studies with oxycodone/naloxone in combination or oxycodone as a single entity
have not been performed. For naloxone, a 24-months oral carcinogenicity study was performed in rats with
naloxone doses up to 100 mg/kg/day. The results indicate that naloxone is not carcinogenic under these
conditions.
Oxycodone and naloxone as single entities show a clastogenic potential in in vitro assays. No similar effects
were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the
mutagenic risk of oxycodone/naloxone hydrochloride prolonged-release tablets to humans at therapeutic
concentrations may be ruled out with adequate certainty.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
5 mg/2.5 mg prolonged-release tablets
Tablet core:
Microcrystalline cellulose,
Lactose monohydrate,
Ammonio methacrylate copolymer,
Povidone,
Talc,
Triacetin,
Stearyl alcohol,
Magnesium stearate,
Anhydrous colloidal silica
Tablet coat:
Hypromellose,
Macrogol,
Talc,
Titanium dioxide (E171),
Brilliant Blue FCF (E133)
10 mg/5 mg prolonged-release tablets
Tablet core:
Microcrystalline cellulose,
Lactose monohydrate,
Ammonio methacrylate copolymer,
Povidone,
Talc,
Triacetin,
Stearyl alcohol,
Magnesium stearate,
Anhydrous colloidal silica
Tablet coat:
Hypromellose,
Macrogol,
Talc,
Titanium dioxide (E171)
20 mg/10 mg prolonged-release tablets
18
Tablet core:
Microcrystalline cellulose,
Ammonio methacrylate copolymer,
Povidone,
Talc,
Triacetin,
Stearyl alcohol,
Magnesium stearate,
Anhydrous colloidal silica
Tablet coat:
Hypromellose,
Macrogol,
Talc,
Titanium dioxide (E171),
Red iron oxide (E172)
40 mg/20 mg prolonged-release tablets
Tablet core:
Microcrystalline cellulose,
Ammonio methacrylate copolymer,
Povidone,
Talc,
Triacetin,
Stearyl alcohol,
Magnesium stearate,
Anhydrous colloidal silica
6.2
Tablet coat:
Hypromellose,
Macrogol,
Talc,
Titanium dioxide (E171),
Red iron oxide (E172),
Yellow iron oxide (E172)
Incompatibilities
Not applicable.
6.3
Shelf life
3 years for the 40 mg/20 mg and 20 mg/10 mg prolonged-release tablets in PVC/PVDC/PVC-Alu blisters.
1 year for the 10 mg/5 mg prolonged-release tablets in PVC/PVDC/PVC-Alu blisters.
9 months for the 5 mg/2.5 mg prolonged-release tablets in PVC/PVDC/PVC-Alu blisters.
6.4
Special precautions for storage
Do not store above 25 °C.
6.5
Nature and contents of container
The prolonged-released tablets are available in child-resistant, perforated unit dose peel-off
PVC/PVDC/PVC-Alu blisters in packs of 10 x 1, 20 x 1, 28 x 1, 30 x 1, 50 x 1, 56 x 1, 60 x 1, 98 x 1 and
100 x 1.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
MARKETING AUTHORISATION HOLDER
<to be completed nationally>
19
8.
MARKETING AUTHORISATION NUMBER(S)
<to be completed nationally>
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<to be completed nationally>
10.
DATE OF REVISION OF THE TEXT
21st January 2016
20